FR3034767A1 - REDUCTION OF THE CARBONYL FUNCTIONS OF CARBOHYDRATES AND AQUEOUS CARBOHYDRATE DERIVATIVES BY SODIUM DITHIONITE - Google Patents

Abstract

The present invention relates to the use of sodium dithionite for the reduction of at least one aldehyde or ketone function of a carbohydrate, a C-glycoside, an oligosaccharide or a water-soluble polysaccharide in the absence of an organic solvent immiscible with water and in the absence of a phase transfer agent and a preparation process comprising contacting a carbohydrate, a C-glycoside of a oligosaccharide or a water-soluble polysaccharide with sodium dithionite.

Description

The present invention relates to the field of reducing water-soluble compounds having a carbonyl function in an aqueous medium. In recent years, the chemical industry has been in a state of flux. The development of eco-responsible processes has become a priority. The chemical industry must therefore succeed in reconciling economic progress, sustainability and eco-compatibility.

One of the major drawbacks of organic chemistry is the massive use of organic solvents, generating considerable quantities of waste. 80 to 90% of the waste generated by the pharmaceutical industry comes from the solvent used. In addition, they are often harmful and volatile. 35% of VOCs released into the atmosphere are solvents and the use of solvent is responsible for half of the greenhouse gas emissions. Thus, one of the major challenges of modern chemistry is the limitation of the use of the solvent. This is the 5th principle of green chemistry. Traditionally, water is rarely used in synthetic chemistry. It poorly solubilizes organic products and reacts with certain functional groups.

On the other hand, water has advantages: it is non-toxic, available, limits the discharges of organic pollutants and has interesting physico-chemical properties (dielectric constant, density of cohesion energy, for example). The implementation of synthetic processes in water is obviously more or less complex depending on the reaction mechanism involved. Its protic appearance and its acidity are thus an obstacle to certain reactions such as reduction. Good numbers of reducing agents are not usable in aqueous medium (hydride, alanes, boranes, metals). Hydrogenation reactions using water-soluble ligands is still marginal. It also faces the use of high pressures of dihydrogen, which constitute an industrial risk.

The inventors of the present invention have demonstrated that it is possible to reduce water-soluble organic compounds such as carbohydrates and carbohydrate derivatives with sodium dithionite under mild conditions and in aqueous medium. Sodium dithionite is a reducing agent with numerous advantages: it is a powerful reducing agent in an aqueous medium (at pH = 7, E = -0.66V, pH = 10, E) = - 1.13V), inexpensive and nontoxic. It is known for its ability to reduce aldehydes and ketones in organic medium by phase transfer. In the context of the present invention, sodium dithionite is used directly in an aqueous medium to reduce carbohydrates or carbohydrate analogs such as fragile and water-soluble C-glycosides. The carbonyl function of the carbohydrate or carbohydrate analogue may be endocyclic, exocyclic or on the carbohydrate anomeric carbon in the form of a hemiacetal. The inventors have in particular demonstrated that sodium dithionite allows the reduction of fragile carbohydrates and / or of industrial interest. The present invention therefore relates to the use of sodium dithionite for the reduction of at least one aldehyde or ketone function of a carbohydrate> a C-glycoside, an oligosaccharide, advantageously a disaccharide or a polysaccharide water-soluble in the absence of an organic solvent immiscible with water and in the absence of a phase transfer agent. Within the meaning of the present invention, the term "aqueous medium") means a medium consisting essentially, as a solvent, of water, and optionally of a water-miscible organic solvent, such as an alcohol, in particular ethanol, propanol such as n-propanol or isopropanol and butanol such as n-butanol. The present invention also relates to the use of sodium dithionite for the reduction of at least one aldehyde, hemiacetal or ketone function of a carbohydrate, a C-glycoside, an oligosaccharide, advantageously a disaccharide or a a water-soluble polysaccharide in the absence of an organic solvent immiscible with water and in the absence of a phase transfer agent of formula (A): wherein: X is selected from the group consisting of CH2 and; n = 0 or 1; 5 m 0, 1 or 2 when n = 0 and m = 0, 1, 2 or 3 when n = 1; Y is selected from the group consisting of OH; (CR2R3) pC (= O) R4; and OR5 R5 is selected from C1 to C12 alkyl; carbohydrate, oligosaccharide; polysaccharide; pyranyl, furanyl or polyol. p = 0, I or 2, R1 is selected from the group consisting of H; CH 2 OH and CH (OH) -CH 2 OH; R2 and R3, identical or different, are selected from the group consisting of H; C1 to C12 alkyl, optionally substituted; aryl, optionally substituted; heteroaryl, optionally substituted; advantageously H; R4 is selected from the group consisting of H; optionally substituted C1 to C12 alkyl; Z, identical or different, are selected from the group consisting of OH; C1 to C12 alkyl, optionally substituted; F; SR6 and NR5R7 and replace 0 or 1 hydrogen atom on 0, 1 or 2 CH2 of the ring when n = 0 or replace 0 or 1 hydrogen atom on 0, 1, 2 or 3 CH2 of the ring when n = 1.

R6 is selected from the group consisting of H, C1 to C12 alkyl: optionally substituted; Ry is selected from the group consisting of N; C1 to C12 alkyl, C (O) R8 where R3 is selected from C1 to C12 alkyl, optionally substituted; aryl, optionally substituted; heteroaryl, optionally substituted; or R5 and R6 Y 3 (CH2) n (Z) m 3034767 4 together with the nitrogen to which they are attached form a 5- or 6-membered ring, optionally substituted, with the proviso that either Y is OH or OR5 and X is O; or Y represents (CR2R3) pC (D) R4.

In the compounds of formula (I) according to the present invention, only one Z group may be present on each of the CH 2 of the ring. Thus, each CH2 of the cycle can be replaced by a CHZ group. For the purposes of the present invention, the term "aryl" means an unsaturated, mono or polycyclic aromatic ring of 5 to 14 members. Among the aryls, mention may be made of phenyl, naphthyl and phenanthrenyl groups. For the purposes of the present invention, the term "heteroaryl" means an unsaturated, mono or polycyclic aromatic ring of 5 to 10 members in which one or more of the CH groups have been replaced by one or more heteroatoms. Among the heteroaryls, mention may especially be made of pydidinyl, pyrrolyl, thiophenyl, furanyl and pyrimydinyl groups. For the purposes of the present invention, the term "optionally substituted" means that one or more hydrogen atoms may be replaced by a group such as a C1 to C3 alkyl group; a hydroxy group; a thio group; An amino group; an alkoxy group such as methoxy, ethoxy, propoxy; a functional group such as CF3; or an atom such as a halogen, especially F. The present invention advantageously relates to the use of sodium dithionite for the reduction of at least one aldehyde, hemiacetal and / or ketone function of a carbohydrate, a C- glycoside, a water-soluble oligosaccharide or polysaccharide in the absence of an organic solvent immiscible with water and in the absence of a phase transfer agent of the following formula (I): Wherein: X is selected from the group consisting of CH2 and; n = 0 or 1; m 0, 1 or 2 when n 0 and m = 0, 1, 2 or 3 when n = 1; Y is selected from the group consisting of OH; (CR2R3) pC (= O) R4; and OR5 R5 is selected from C1 to C12 alkyl; carbohydrate, oligosaccharide; polysaccharide; pyranyl, furanyl or polyol. p = 0, 1 or 2, R1 is selected from the group consisting of H; CH 2 OH and CH (OH) -CH 2 OH; R 2 and R 3, identical or different, are selected from the group consisting of H; C1 to C12 alkyl, optionally substituted; aryl, optionally substituted; heteroaryl, optionally substituted; advantageously H; R4 is selected from the group consisting of H; C1 to C12 alkyl, optionally substituted; Z, identical or different, are selected from the group consisting of O-1; C1 to C12 alkyl, optionally substituted; F; SRG and NR6R7 and replace 0 or 1 hydrogen atom on 0, 1 or 2 0H2 of the ring when n = 0 or replace 0 or 1 hydrogen atom on 0, 1, 2 or 30H2 of the ring when n = 1. RG is selected from the group consisting of H, optionally substituted C1 to C12 alkyl; R7 is selected from the group consisting of H; C1 to C12 alkyl, C (= O) R8 where R8 is selected from C1 to C12 alkyl, optionally substituted; aryl, optionally substituted; heteroaryl, optionally substituted; Or R5 and R6 together with the nitrogen to which they are attached form a 5- or 6-membered, optionally substituted ring, with the proviso that either Y is OH or OR5 and X is O; either Y represents (CR2R3) pC (= O) R4.

The carbohydrates, C-glycosides, oligosaccharides or polysaccharides according to the present invention can be any epimer of the corresponding compound of formula (I) or a mixture of several epimers. In other words, the groups R 1, Z and Y may be in front of or behind the mean plane of the 5- or 6-membered heterocycle or carbocycle. The reduction of the masked aldehyde function in hemiacetal form present in carbohydrates allows an efficient and simple access to the polyols used as sweeteners. Examples of structures reducible with Na2S204 are reducing monosaccharides or disaccharides such as xylose, erythrose, isomaltose, maltose, glucose, mannose and lactose. The reduction of at least one aldehyde, hemiacetal and / or ketone function is carried out with 1 to 15 moles, advantageously from 4 to 10 moles, in particular about 5 moles of sodium dithionite per mole of aldehyde, hemiacetal and / or ketone function. reduce.

In an advantageous embodiment, the use of an antioxidant makes it possible to avoid the use of an excess of sodium dithionite. The reduction of at least one aldehyde, hemiacetal and / or ketone function is carried out in the presence of a base, which may or may not be soluble in water. The use of a water-insoluble base makes it possible in particular to eliminate it more easily at the end of the reaction, for example by filtration, to limit the neutralization treatments and to limit the corrosion of the reactors. Advantageously, said soluble base is chosen from hydroxides such as NaOH and KOH, and hydrogenocarbonates such as NaHCO3 and KHCO3. The water-insoluble base is advantageously chosen from calcium carbonate, hydrotalcite and biobased calcium bases derived from the calcination of plants, calcifying algae or mollusc shells described in application WO 2015/036714. advantageously the biosourced calcium bases treated at 900 ° C. or at a temperature below 500 ° C. according to the method described in the application WO 2015/036714. More preferably, the base is selected from hydrogenocarbonates or biobased calcium bases. Advantageously, the pH of the aqueous solution in which the reduction is carried out is between 7 and 14, advantageously between 8 and 12.

Advantageously, the base is present in excess relative to the sodium dithionite, advantageously in a ratio of between 50 1 and 1: 1, in particular from 10: 1 to 1: 1, preferably from 1.2: 1. Advantageously, the base and sodium dithionite are added simultaneously to an aqueous solution of the carbohydrate, C-glycoside, oligosaccharide or polysaccharide. For example, the base and the sodium dithionite may be mixed separately from the carbohydrate, oligosaccharide or polysaccharide and added to the carbohydrate, oligosaccharide or polysaccharide in solution in the aqueous medium.

Advantageously, the base and the sodium dithionite are added very slowly to the aqueous solution of the carbohydrate, oligosaccharide or polysaccharide, in particular over a period of between 1 hour and 24 hours, advantageously between 2 hours and 6 hours, in particular over a period of 4 hours. The base and the sodium dithionite are advantageously added in portions to the carbohydrate, C-glycoside, oligosaccharide or polysaccharide to be reduced, especially at intervals of 10 minutes to 3 hours, advantageously from 30 minutes to 2 hours. especially hourly or continuously for the duration of the reaction. By "added in portions" is meant for the purpose of the present invention that the total amount of sodium and base dithionite is divided into equal or non-equal parts, each of these parts being added to the carbohydrate solution, the oligosaccharide or polysaccharide at regular or non-regular intervals. The reduction of at least one aldehyde, hemiacetal or ketone function is carried out at a temperature of between 20 and 110 ° C, advantageously between 40 and 100 ° C, in particular at a temperature of 90 ° C.

According to a first embodiment, the present invention relates to the use of sodium dithionite for the reduction of at least one aldehyde, hemiacetal and / or ketone function of a carbohydrate, a C-glycoside, a oligosaccharide or a water-soluble polysaccharide in the absence of a water-immiscible organic solvent and in the absence of a phase transfer agent of the following formula (II): ## STR2 ## in which which: R1, X, Y, Z and m are as defined in formula (I). The water-soluble carbohydrate, C-glycoside, oligosaccharide or polysaccharide may be a compound of formula (IIa) wherein X, R1 and Y are as defined in formula (I). Advantageously, X is O. The water-soluble carbohydrate, C-glycoside, oligosaccharide or polysaccharide may be a compound of formula (IIb): wherein R1 is H or CH2OH and X and Y are as defined in US Pat. Formula 1). Advantageously, X is O. Advantageously, the water-soluble carbohydrate, C-glycoside, oligosaccharide or polysaccharide is a compound of formula (IIb1): ## STR2 ## in which X is as defined in formula (I), R1 is H or CH2OH, advantageously H, and Y is (CH2) pC (= O) R4 where R4 is as defined in formula (I) - Examples of compounds of formula (II) are the following: ## STR1 ## wherein: ## STR1 ## ## STR2 ## ; HO HO HO HO HO HO ow-OH. OH ; 514 OH; In a second embodiment, the present invention relates to the use of sodium clithionite for the reduction of sodium hydroxide. at least one aldehyde and / or ketone function of a water-soluble carbohydrate, C-glycoside, oligosaccharide or polysaccharide in the absence of an organic solvent immiscible with water and / or a phase transfer agent of the following formula (III): (Z) wherein R1, X, Y, Z and m are as defined in formula (I). The carbohydrate, C-glycoside, oligosaccharide or water-soluble polysaccharide may be a compound of formula (IIIa): ## STR2 ## wherein X, R 1 and Y are as defined in formula (1). Advantageously, X is O. The water-soluble carbohydrate, C-glycoside, oligosaccharide or polysaccharide may be a compound of formula (IIIb): wherein R 1 is CH 2 OH or CH (OH) CH 2 OH, X and Y are as defined in formula (I). Advantageously, X is O.

Examples of compounds of formula (III) are as follows: The present invention also relates to a process for the preparation of a compound of formula (IV): (Z) m comprising the step of contacting a compound of formula (I) wherein X is O and Y is OH, carbohydrate, oligosaccharide or oligosaccharide, advantageously OH with sodium dithionite in an aqueous medium in the absence of a non-organic solvent -miscible with water and a phase transfer agent. The present invention also relates to a process for the preparation of a compound of formula (V): (Z) n1 comprising the step of bringing into contact a compound of formula (I) in which Y represents C (R2R3) C (= O) R4 with sodium dithionite in an aqueous medium in the absence of an organic solvent immiscible with water and in the absence of a phase transfer agent. Advantageously, in the compound of formula (1) for the preparation of the compound of formula (V), X is as defined in formula (I), R1 is H or CH2OH and Y is (CH2) pC (= 0) R4 where p and R4 are as defined in formula (I). In the processes for preparing compounds of formula (IV) and (V) as described above, preferably, said soluble base is selected from hydroxides such as NaOH and KOH, hydrogen carbonates such as NaHCO3 and KHCO3. The water-insoluble base is advantageously chosen from calcium carbonate, hydrotalcite and biobased calcium bases derived from the calcination of plants, calcifying algae or mollusc shells described in application WO 2015 / 036714, advantageously the biosourced calcium bases treated at 900 ° C or at a temperature below 500 ° C according to the method described in the application WO 2015/036714. More preferably, the base 5 is selected from hydrogenocarbonates or bio-based calcium bases. In the processes for preparing the compounds of formula (IV) and (V), the pH of the aqueous solution in which the reduction is carried out is between 7 and 14, advantageously between 8 and 12. In the processes for the preparation of the compounds of Formula (IV) and (V), advantageously, the base is present in excess relative to sodium dithionite, advantageously in a ratio of between 50: 1 and 1: 1, in particular from 10: 1 to 1: 1, Preferably, in the processes for the preparation of the compounds of the formula (IV) and (V), the base and the sodium dithionite are added simultaneously to an aqueous solution of the carbohydrate, the C-glycoside , oligosaccharide or polysaccharide. For example, the base and the sodium dithionite may be mixed separately from the carbohydrate, oligosaccharide or polysaccharide and added to the carbohydrate, oligosaccharide or polysaccharide in solution in the aqueous medium. In the processes for preparing the compounds of formula (IV) and (V), the sodium base and dithionite are advantageously added in portions to the carbohydrate, C-glycoside, oligosaccharide or polysaccharide to be reduced, in particular to intervals of 10 minutes to 3 hours, preferably 30 minutes to 2 hours, especially 1 hour or continuously for the duration of the reaction. In the processes for preparing the compounds of formula (IV) and (V) as described above, the contacting step is advantageously followed by a heating step at a temperature between 20 and 110 ° C. preferably between 40 and 100 ° C, especially at a temperature of 90 ° C. In the processes for preparing the compounds of formula (IV) and (V) as described above, the product is purified at the end of the reaction. Product purification methods are known to those skilled in the art. Advantageously, the aqueous solution is lyophilized and the product of formula (IV) or (V) is redissolved in an aprotic polar solvent, advantageously anhydrous, such as an alcohol, advantageously ethanol or isopropanol. Of course, the reduction product can be purified by methods well known to those skilled in the art such as preparative HPLC, reverse phase chromatography or recrystallization.

EXAMPLES EXAMPLE 1: Reduction of D-xylose to D-xylitol OH 1-10 Na2S204 NaHCO3 01-1O1-1H2O, 90 ° C, 20 h In a 25 mL flask equipped with a magnetic bar and a condenser, under an N 2 stream, an aqueous solution (5 ml) composed of 546 mg (6.5 mmol) of NaHCO 3 and 244 mg (1.4 mmol) of Na 2 S 2 O 4, is added to 758 μL (1 mmol) of a 25% aqueous solution of D-xylose (mN). A clear pale yellow solution is obtained. This is heated at 90 ° C., with stirring and under a stream of N 2. After 1 h of heating, a new addition of 244 mg (1.4 mmol) Na 2 S 2 O 4 is made. This addition is then repeated 2 more times, each addition being spaced from the previous one hour. After 15 hours of reaction, the medium is lyophilized and then the dry residue is taken up in anhydrous ethanol (5 × 20 ml). The concentration of the ethanol extract provides D-xylitol in 83% yield. Example 2: Reduction of 4,8-anhydro-1,3-cHdeoxy-D-glycero-L-manno-2-nonulose (1) in aqueous solution 20 OH 0-e-OH In a 25 mL flask, equipped with A magnetic bar and a condenser, under a flow of N 2, an aqueous solution (5 ml) composed of 546 mg (6.5 mmol) of NaHCO 3 and 244 mg (1.4 mmol) of Na 2 S 2 O 4 is added very slowly. at 758 μL (1 mmol) HO Na 2 S 2 O 3 NaHCO 3 HO 0 H 2 O, 90 ° C, 20 h H "2 of an aqueous solution of 4,8-anhydro-1,3-dideoxy-D-glycero L-manno-2-nonulose 1 to 25% (mN). A clear pale yellow solution is obtained. This is heated at 90 ° C., with stirring and under a stream of N 2. After 1 h of heating, a new addition of 244 mg (1.4 mmol) Na 2 S 2 O 4 is made. This addition is then repeated 2 more times, with each addition spaced from the previous one hour. After 20 hours of reaction, the medium is freeze-dried and the dry residue is taken up in anhydrous ethanol (5 × 20 ml). The concentration of the ethanolic extract provides the reduction product 2. Sodium dithionite is a very good substitute for NaBH4 and catalytic hydrogenation under pressure. 10

Claims (10)

REVENDICATIONS1. Use of sodium dithionite for the reduction of at least one aldehyde, hemiacetal or ketone function of a water-soluble carbohydrate, C-glycoside, oligosaccharide or polysaccharide in the absence of an organic solvent immiscible with water and in the absence of a phase transfer agent. The use according to claim 1, wherein the carbohydrate, C-glycoside, oligosaccharide or polysaccharide is a compound of formula (I): (Z) m wherein: X is selected from the group consisting of CH2 and O; n = 0 or 1; m 0, 1 or 2 when n 0 and m = 0, 1, 2 or 3 when n = 1; Y is selected from the group consisting of OH; (CR2R3) pC (= O) R4; and OR5 R5 is selected from C1 to C12 alkyl; carbohydrate, oligosaccharide; polysaccharide; pyranyl, furanyl or polyol. p = 0, 1 or 2, preferably 1 or 2, R1 is selected from the group consisting of H; CH 2 OH and CH (OH) -CH 2 OH; R2 and R3, identical or different, are selected from the group consisting of H; C1 to C12 alkyl, optionally substituted; aryl, optionally substituted; heteroaryl, optionally substituted; advantageously H; R4 is selected from the group consisting of H; optionally substituted C1 to C121 alkyl; Z, identical or different, are selected from the group consisting of OH; C1 to C12 alkyl, optionally substituted; F; SR6 and NR6R7 and replace 0 or 1 hydrogen atom on 0, 1 or 2 CH2 of the ring when n = 0 or replace 0 or 1 hydrogen atom on 0, 1, 2 or 3 CH2 of the ring when n = R6 is selected from the group consisting of H, C1-C12 alkyl, optionally substituted; R7 is selected from the group consisting of H; C1 to C12 alkyl, C (O) R8 where R8 is selected from C1 to C12 alkyl, optionally substituted; aryl, optionally substituted; heteroaryl, optionally substituted; or R6 and R6 together with the nitrogen to which they are attached form a 5- or 6-membered ring, optionally substituted, provided that either Y is OH or OR5 and X is O; either Y represents (CR2R3) pq = 0) R4. 3. Use according to one of claims 1 or 2 wherein the compound has the following formula (II): (Z) wherein R1, X, Y, Z and m are as defined in claim 2. 4. Use according to claim 3 wherein m = 3, Z is OH, X, R1 and Y are as defined in formula (1). 5. Use according to one of claims 3 or 4, wherein R1 is H or CH2OH and Y is (CH2) C (O) R4. 6. Use according to one of claims 1 or 2, wherein the compound of formula (I) has the following formula (111) in which R 1, X, Y, Z and n are as defined in claim 2. 7. Process for preparing a compound of formula (IV): (Z) m comprising the step of bringing into contact a compound of formula (I) as defined in claim 2: (Z) m wherein X is 0 and Y is OH or OR5 with sodium dithionite in an aqueous medium in the absence of a water immiscible organic solvent and in the absence of a phase transfer agent. 8. Process for preparing a compound of formula (V): (Z) m comprising the step of bringing into contact a compound of formula (I) as defined in claim 2: (Z) m wherein Y is C (R 2 R 3) C (= O) R 4, with sodium dithionite in an aqueous medium in the absence of an organic solvent immiscible with water and in the absence of a surfactant. phase transfer. 9. Method according to one of claims 7 or 8, wherein the step of contacting the compound of formula (I) and sodium dithionite is carried out in the presence of a water-soluble or non-soluble base , advantageously chosen from hydroxides, hydrogenocarbonates, calcium carbonate, hydrotalcite and biobased calcium bases derived from the calcination of plants, calcifying algae or shellfish shells. 10. Method according to one of claims 7 to 9, wherein the contacting is followed by a heating step at a temperature between 20 and 110 ° C, preferably between 40 and 100 ° C, especially at a temperature 90 ° C.